Herpes simplex viruses (HSV) cause a wide spectrum of diseases ranging from mild to severe mucosal lesions, keratitis, and encephalitis. Both HSV types 1 and 2 are widely distributed in the western adult population, with reported exposure rates to HSV-1 estimated to be as high as 90%. The recent and rapid increase in the number of genital HSV infections is reflected by serology studies which indicate that 15-35% of the North American adult population have been exposed to HSV 2.
The major effort to develop antiherpetic drugs has historically centered on nucleoside analog inhibitors of HSV DNA polymerase. All currently used therapies are nucleoside analogs, acyclovir being the prime example. Oral or IV acyclovir is the therapy of choice for most infections. Topical acyclovir, vidarabine or idoxuridine are all used for herpes keratitis, the leading cause of corneal blindness in this country. However, considering the complex replication cycle and large number of virally encoded proteins, other potential targets for antiviral drugs must exist. HSV ribonucleotide reductase (RR) is one such target; the viral-specified enzyme is markedly different from mammalian counterparts. HSV-RR catalyzes the reduction of the four ribonucleotides to the corresponding deoxyribonucleotides required for DNA replication. Published analysis of viral RR mutants indicated that the enzyme is not essential for growth of herpes in culture (Goldstein and Weller, Virology 166: 41 (1988)), but is essential in vivo (Spector, Pharmaceutical Therapy, 31, 295 (1985)). Herpes RR inhibitors have been shown to possess antiherpetic activity per se (Shipman et al., Antiviral Research, 6: 197 (1986)) and also to potentiate or synergize the action of acyclonucleoside antiviral agents (Spector et al., Proc. of the Nat. Acad. Of Sci., 86: (1989)).
Dutia et al., Nature 321: 439-441 (1986) and Cohen et al., Nature 321: 441-443 (1986) and U.S. Pat. No. 4,795,740, both disclosed that the nonapeptide Tyr Ala Gly Ala Val Val Asn Asp Leu, inhibited in vitro the activity of this enzyme. In addition Dutia et al., op. cit., also disclosed that its 8-desalanine homolog, Tyr gly Ala Val Val Asn Asp Leu, also inhibited in vitro the activity of this enzyme. Gaudreau et al., J. Biol. Chemistry, 262 12413 (1987) disclosed structure activity studies of analogs of the nonapeptide described above.